Formulations comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol

ABSTRACT

A solid pharmaceutical composition suitable for oral administration, comprising:
         (a) a SI P receptor modulator;   (b) a filler, and   (c) a cyclodextrin.

The present invention relates to pharmaceutical compositions comprisinga S1P receptor modulator selected from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form, in a pharmaceutically acceptablesalt form (fingolimod, FTY720) and a phosphate derivative thereof(FTY720-phosphate), as well as process for their production and use ofthe pharmaceutical compositions.

2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride becamethe first oral drug approved to reduce relapses and delay disabilityprogression in patients with relapsing forms of multiple sclerosis (MS).Before, the MS drugs on the markets were all delivered by frequentinjections, either intravenously or intra-muscularly, varying fromonce-per-day to once-per-week depending on the drug.

Fingolimod is believed to reduce the number of lymphocytes circulatingIn the blood stream by reversibly trapping a proportion of them in thelymph nodes. Consequently, the number of activated lymphocytes reachingthe brain is decreased, resulting in reduced inflammatory destruction.Fingolimod efficacy in the treatment of multiple sclerosis has beenshown in humans (e.g. as described in “FTY720 therapy exertsdifferential effects on T cell subsets in multiple sclerosis”. MehlingM, et al., Neurology. 2008 October 14; 71(16):1261-7; and “Oralfingolimod (FTY720) for relapsing multiple sclerosis”. Kappos L, AntelJ, Comi G, Montalban X, O'Connor P, Polman C H, Haas T, Korn A A,Karlsson G, Radue E W; FTY720 D2201 Study Group. N Engl J Med. 2006 Sep.14; 355(11)1124-40.).

Pharmaceutical compositions comprising2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in apharmaceutically acceptable salt form (fingolimod) or as a phosphatederivative, in particular in form of oral formulations, are known in theart, e.g. as described in EP1613288A the content of which beingincorporated herein by reference. EP1613288A describes a tabletcomprising 1.4 mg of the hydrochloride salt of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, and capsulescomprising 0.56 mg, 1.0 mg or more of the hydrochloride salt of2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol.

Solid state forms of 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diolhydrochloride are described in the art. For example, IPCOM000204549Ddescribes crystals of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride prepared by mixing about 30 wt % of2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride withabout 75 wt % α- or β-cyclodextrin in water and then evaporating waterwith ethanol to dryness, and drying the solid. There is no indication ofusing a low amount of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride as in the present invention, evenles preparing a composition comprising a low amount of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride whichcomplies with all the requirements of a pharmaceutical compositions, asnow obtained with the compositions of the present invention.

However there still exists a need for preparing an improvedpharmaceutical composition for oral administration containing2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-dial, in free form, in apharmaceutically acceptable salt form or as a phosphate derivative. Inparticular there is a need for preparing a pharmaceutical compositionwhich can be used to administer on a safe and prolonged way a low amountof the compound, i.e. a composition which is stable, homogeneous andshows appropriate content uniformity, while containing 0.5 mg or less of2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol.

Obtaining a composition that is stable, homogeneous, e.g. which showsappropriate blend content uniformity and/or drug content uniformity isparticularly critical for a composition containing a low amount of theactive substance since in such a case even minor modifications on thedrug amount, e.g. due to degradation or lack of uniformity, may lead tobe a significant impact on the total content of the drug that thepatient consumes. With a limited amount of drug in the composition, evena limited degradation thereof may result in administering to the patienta drug amount that is too low to provide the desired therapeuticbenefit. So it may be paramount for the patient to receive the adequatedrug dosage every time he (or she) is taking his (or her) medication inorder to ensure long term efficacy of the drug. The lower the drugcontent is, the more these requirements are difficult to meet. Forexample, it can be shown that the stability of solid compositioncomprising fingolimod is dependent upon the concentration of the drug,and therefore the lower the concentration of the compound, the more itbecomes sensitive to degradation.

Furthermore, when formulating an oral composition containing2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol, in free form, in apharmaceutically acceptable salt form or as a phosphate derivative, theperson skilled in the art is confronted with several difficulties due tothe nature and characteristics of the compound. Fingolimod is instablein presence of many excipients, especially at high temperatures orhumidity conditions: many pharmaceutically acceptable excipients are notcompatible with fingolimod, i.e. when mixed thereto induce impurities ordegradation products at a level above the acceptable level for apharmaceutical composition, according to the Regulatory HealthAuthorities. Fingolimod, in particular when micronized, is also staticin nature and has the tendency to stick to metal surfaces, leading tonon negligible drug segregation during the formulation manufacture. Thismay pose problems when preparing large scales of fingolimod-containingcompositions, in particular compositions comprising low dosage of thedrug, for example 0.5 mg or less.

It has now been found that by using a stabilizer, for example acyclodextrin, it becomes possible to prepare pharmaceutical compositionsfor oral administration comprising a low amount of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form, in apharmaceutically acceptable salt form or as a phosphate derivative,which show an appropriate content uniformity and are physically stableeven during extended periods of time. In particular it has becomepossible to prepare stable compositions comprising less than 0.5 mg of2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol, e.g. 0.25 mg orless. Unexpectedly, despite the low amount of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, the interaction offingolimod with the other excipients that are needed for preparing asolid composition for oral administration are now minimized.

Furthermore, the segregation which otherwise occurs during themanufacturing process and leads to a partial loss of the drug substance,is reduced. Thus compositions comprising a low amount of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, e.g. 0.5 mg or less,can be prepared on large scales with limited variations in the drugcontent amongst the different batches.

In particular, the use of a stabilizer, for example a cyclodextrin orderivative thereof, in the formulation process permits blending of thedifferent ingredients (active substance and excipients) in such a waythat a mixture of uniform particle size is obtained and thus an evendistribution of the drug content in the final composition is ensured.

The invention provides solid pharmaceutical compositions suitable fororal administration, and comprising

-   -   a) a compound selected from        2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a        pharmaceutically acceptable salt thereof, and a phosphate        derivative thereof,    -   b) a filler,    -   c) a stabilizer, and optionally    -   d) a binder and/or a lubricant.

The compound of the invention is selected from2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form, apharmaceutically acceptable salt thereof, and a phosphate derivativethereof, e.g. is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol infree form or a pharmaceutically acceptable salt thereof.

The structure of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol(FTY720) is shown below:

The structure of phosphate derivative thereof is shown below:

According to the present invention, the compound may be a salt selectedfrom ascorbate, oxalate, phosphate, mandelate, adipate, ethanesulfonate,naphtalene-1,5-disulfonate, naphtalene-1-sulfonate,naphtalene-2-sulfonate, aspartate, e.g. L-aspartate, benzoate,4-acetamidobenzoate, (+) camphorate, (+)camphor-10-sulfonate, decanoate,hexanoate, octanoate, cinnamate, dodecylsulfate, ethane-1,2-disulfonate,2-hydroxyethanesulfonate, glutarate, lactate, e.g. DL-lactate,1-hxdroxy-2-naphthoate, laureate, salicylate, hydrochloride, tartrate,mesylate, citrate, benzoate, succinate, malonate, acetate, propionatesalts and mixture thereof. The salt is optionally crystalline.

In one specific embodiment of the invention, the salt is hydrochloride.

The composition of the invention may contain 0.01 to 20% by weight ofthe compound of the invention, for example 0.1 to 10%, e.g. 0.05 to 10%,e.g. 0.05 to 5%, e.g. 0.05 to 2%, e.g. 0.1 to 5%, e.g. 0.1 to 2%, e.g.0.1 to 5%, e.g. 0.1 to 2%, e.g. 0.5 to 5%, e.g. 0.5 to 2%, e.g. 0.8 to1.3%, e.g. 0.9 to 1.2%, by weight, based on the total weight of thecomposition, or e.g. 0.1 to 0.5%, e.g. 0.15 to 0.5, e.g. 0.2 to 0.3% byweight, based on the total weight of the composition. For example, thecomposition of the invention comprises about 1% by weight of the S1Preceptor modulator, based on the total weight of the composition, forexample 1% by weight plus or less 0.15% of the S1P receptor modulator,based on the total weight of the composition. For example about 0.6% byweight, for example about 0.5% by weight, for example about 0.4% byweight, for example about 0.3% by weight, for example about 0.25% byweight, for example about 0.2% by weight, for example about 0.15% byweight, based on the total weight of the composition. In anotherexample, the composition of the invention comprises less than 2% byweight, less than 1.5% by weight, less than 1% by weight of the S1Preceptor modulator, e.g. less than 0.5% by weight, e.g. less than 0.4%by weight e.g. less than 0.3% by weight, e.g. less than 0.2% by weight,based on the total weight of the composition

According to the invention, the stabilizer may be selected from acyclodextrin or a derivative thereof, glycine HCl, sodium bicarbonate,and mixture thereof. In one embodiment of the invention, the stabilizercomprises a cyclodextrin or a derivative thereof, or consists of acyclodextrin or a derivative thereof, e.g. as herein below defined.

Under cyclodextrin and derivative thereof it is meant e.g. a naturalcyclodextrin, a branched cyclodextrin, an alkyl-cyclodextrin or ahydroxyalkyl-cyclodextrin. For example cyclodextrin or and derivativethereof may be α-cyclodextrin; β-cyclodextrin, γ-cyclodextrin;hydroxypropyl-cyclodextrin such as hydroxypropyl-α-cyclodextrin orhydroxypropyl-β-cyclodextrin; sulfobutylether β-cyclodextrin;dodecakis-2,6,O-methyl-α-cyclodextrin;tetradecakis-2,6,O-methyl-β-cyclodextrin;hexadecakis-2,6,O-methyl-γ-cyclodextrin;tetradecakis-2,6,O-ethyl-β-cyclodextrin; α-cyclodextrin partiallyetherized with 2-hydroxypropyl; β-cyclodextrin partially etherized with2-hydroxypropyl; branched α-cyclodextrin and branched β-cyclodextrinwhere glucose or maltose has been bound via α-1,6 glucoside bound.

In a specific embodiment of the invention, cyclodextrin or derivativethereof is hydroxypropyl-α-cyclodextrin or hydroxypropyl-β-cyclodextrin,e.g. hydroxypropyl-β-cyclodextrin (also herein referred as HP-β CD).

In another embodiment of the invention, cyclodextrin and derivativethereof is not α-cyclodextrin nor β-cyclodextrin.

The composition of the invention, e.g. the final product for oraladministration or an intermediate form thereof may contain 0.1 to 30%,e.g. 0.2 to 15% by weight of the stabilizer, e.g. cyclodextrin or aderivative thereof, for example 0.4 to 10%, e.g. 0.5 to 10%, e.g. 0.6 to10%, e.g. 1.5 to 8% or 1.5 to 3.5%, e.g. 1.0 to 5% or 1.0 to 3%, e.g.0.1 to 10%, e.g. 0.1 to 8%, e.g. 0.1 to 5%, e.g. 0.1 to 3%, e.g. 0.1 to1%, e.g. 0.5 to 1%, by weight of the stabilizer, e.g. cyclodextrin,based on the total weight of the composition. For example thecomposition of the invention may contain about 5%, e.g. about 4%, e.g.about 3%, e.g. about 2.5%, e.g. about 2%, e.g. about 1.5%, e.g. about1%, e.g. about 0.5% by weight of the stabilizer, e.g. cyclodextrin,based on the total weight of the composition, e.g. the final product fororal administration or an intermediate form thereof

According to the invention, the stabilizer, e.g. the cyclodextrin, maybe present in an amount about 7, e.g. about 6, e.g. about 5 times, e.g.about 4 times (weight ratios) greater than the amount of the S1Preceptor modulator of the invention, e.g. than the amount of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceuticallyacceptable salt thereof, in a weight to weight ratio. For example, theamount of the stabilizer, e.g. the cyclodextrin, may be about 5 timehigher, e.g. four times higher, e.g. three times higher, than the amountof the S1P receptor modulator of the invention, e.g. than the amount of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or as apharmaceutically acceptable salt thereof, e.g.2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride, in aweight to weight ratio.

According to the invention, the stabilizer, e.g. the cyclodextrin, maybe present in an amount about 0 to 4 times, e.g. about 0.2 to 3 times,e.g. about 0.4 to 3 times, e.g. about 0.4 times, e.g. about 1 time, e.g.about 1.5 times, e.g. about 2 times, e.g. about 2.5 times, e.g. about 3times, e.g. about 3.5 times (molar ratios) greater than the amount ofthe S1P receptor modulator of the invention, e.g. than the amount of2-amino-2-[2-(4 octylphenyl)ethyl]propane-1,3-diol or a pharmaceuticallyacceptable salt thereof, in a molar to molar ratio. For example, theamount of the stabilizer, e.g. the cyclodextrin, may be about 3 times or2 times higher, than the amount of the S1P receptor modulator of theinvention, e.g. than the amount of2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceuticallyacceptable salt thereof, in a molar to molar ratio. In one embodimentthe molar ratio of the cyclodextrin to2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free or as apharmaceutically acceptable salt thereof, e.g. as hydrochloride, is ofabout 0.6 to 1.2, e.g. is about 0.7, e.g. about 0.8, e.g. about 0.9,e.g. about 1.0, e.g. about 1.1, e.g. about 1.2.

According to the invention, the filler may be selected from a sugaralcohol, microcrystalline cellulose (e.g. Avicel®), methylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, starch (e.g. cornstarch, pregelatinized starch), dicalcium phosphate, and mixturethereof.

In a specific embodiment of the invention, the filler is selected from asugar alcohol, microcrystalline cellulose (e.g. Avicel®) and mixturethereof, for example the filler consists of one or more sugar alcohol ora mixture of one sugar alcohol with microcrystalline cellulose, e.g. amixture of mannitol with microcrystalline cellulose, e.g. mannitol withAvicel®. According to the invention, the weight ratio sugar alcohol(e.g. mannitol or mixture of mannitol with another sugar alcohol) tomicrocrystalline cellulose may be of about 5:95, e.g. about 10:90, e.g.about 15:85, e.g. about 20:80; e.g. about 25:75; e.g. about 30:70; e.g.about 35:65; e.g. about 40:60 ; e.g. about 45:55;; e.g. about 50:50;e.g. about 55:45; e.g. about 60:50; e.g. about 65:45; e.g. about 70:00.In a specific embodiment the weight ratio mannitol: Avicel is of about10:90, e.g. about 15:85, e.g. about 20:80; e.g. about 25:75, e.g. about30:70, e.g. about 35:65.

In another embodiment, the filler comprises a mixture of one or moresugar alcohol with another filler as mentioned above. For example thefiller is a mixture of one or more sugar alcohol with a second componentselected from methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; e.g. the filler is a mixture of one or more sugaralcohol with hydroxypropylcellulose. In one specific example, the fillercomprises a mixture of mannitol and hydroxypropylcellulose.

In another embodiment of the invention, the filler is or comprisesstarch, e.g. corn starch or pregelatinized starch or a mixture thereof.For example, the weight ratio sugar alcohol (e.g. mannitol or mixture ofmannitol with another sugar alcohol) to starch (e.g. corn starch orpregelatinized starch or a mixture thereof) is of about 50:50; e.g. ofabout 55:45; e.g. of about 60:40; e.g. of about 65:35; e.g. of about70:30; e.g. of about 75:25; e.g. of about 80:20; e.g. of about 85:15;e.g. of about 90:10. In a specific embodiment the weight ratio mannitol:starch, e.g. mannitol: corn starch or pregelatinized starch is of about55:45; e.g. of about 60:40; e.g. of about 65:35; e.g. of about 70:30;e.g. of about 75:25; e.g. of about 80:20; e.g. of about 85:15.

The filler may be present in an amount of from about 0.1 to about 90% byweight, e.g. about 1 to about 30%, e.g. about 10 to about 30% by weight;e.g. about 15 to about 30% by weight; e.g. about 20 to about 30% byweight, e.g. about 10%, e.g. about 15%, e.g. about 20%, e.g. about 25%,e.g. about 30%, e.g. about 35%, e.g. about 40%, e.g. about 45%, e.g.about 50%, e.g. about 55%, e.g. about 60%, e.g. about 65%, by weight,based on the total weight of the composition, e.g. in the final productor an intermediate form thereof.

According to the invention, the disintegrants may be selected fromcrosspovidone, strach (e.g. corn starch, pregelatanised starch ormixture thereof), crosscarmellose sodium and mixture thereof. In oneexample, the disintegrant may comprise about 1 to 6 weight %, e.g. 2 to5 weight %, e.g. 3 to 4 weight % of crosspovidone. It may comprise about4 to 12 weight %, e.g. about 5 to10 weight %, e.g. about 6 to 8 weight %of starch (e.g. corn starch, pregelatanised starch or mixturethereof).The desintegrant may comprise

In one embodiment, the disintegrant may comprise a mixture ofcrosspovidone, pregelatanised starch and crosscarmellose sodium. Forexample, it may comprise about 5 to 30 weight %, e.g. about 10 to 25weight %, e.g. about 15 to 20 weight % of crosscarmellose sodium).

According to the invention, the sugar alcohol may be selected frommannitol, maltitol, inositol, xylitol, lactitol, and mixture thereof.For example, the sugar alcohol is a substantially non-hygroscopic sugaralcohol, e.g. mannitol, e.g. D-mannitol.

A single sugar alcohol may be used, or a mixture of two or more sugaralcohols, e.g. a mixture of mannitol and xylitol, e.g. in a ratio of 1:1to 4:1.

In a particular embodiment, the sugar alcohol is prepared from aspray-dried composition, e.g. mannitol composition, having a highspecific surface area. The use of this type of mannitol composition mayassist in promoting uniform distribution of the S1P receptor modulatorthroughout the mannitol in the composition. A higher surface area may beachieved by providing a sugar alcohol, e.g. mannitol, preparationconsisting of particles having a smaller mean size and/or a roughersurface on each particle. The use of a spray-dried sugar alcohol, e.g.mannitol, e.g. with a mean particle size of 300 μm or less, has alsobeen found to improve compressibility and hardness of tablets formedfrom the composition.

In one embodiment of the invention, the single point surface area of thesugar alcohol preparation, e.g. mannitol, is 1 to 7 m²/g, e.g. 2 to 6m²/g or 3 to 5 m²/g. The mannitol preparation may suitably have a meanparticle size of 10 to 400 μm, e.g. 10 to 300 μm, e.g. 150 to 250 μm.For example, the mannitol of the invention may have a mean particle sizeof 60 μM, 120 μM, 180 μM, 200 μM, 300 μM or 400 μM.

For example, the mannitol may have particle of 60 um in average, or themannitol may be Parteck M200. In a specific embodiment, a mixture ofmannitol can be used, e.g. a mixture of mannitol (60 um) and mannitol(180 um), or mannitol (60 um) and mannitol (120 um). For example, themannitol can be a mixture of mannitol (200 um) with another mannitol,e.g. with mannitol (180 um), mannitol (60 um), mannitol (120 um) or amixture thereof.

The ratios Mannitol (60 um): Mannitol (180 um) may vary from e.g. 1:0 to2:0, e.g. from 1:2 to 1:5. For example, it may be about 20% of Mannitol(60 um): 70% of Mannitol (180 um); e.g. about 30% of Mannitol (60 um):60% of Mannitol (180 um).; e.g. about 40% of Mannitol (60 um): 50% ofMannitol (180 um).

The ratios Mannitol (200 um): other mannitol (e.g. Mannitol 180 um) mayvary from e.g. 1:0 to 2:0. For example, it may be about 20% of Mannitol(200 um): 80% of the other forms of mannitol; e.g. about 30% of Mannitol(200 um): 70% of the other forms of mannitol; e.g. about 40% of Mannitol(60 um): 60% of the other forms of mannitol.

The mannitol may have a bulk density of 0.4 to 0.6 g/mL, e.g. 0.45 to0.55 g/mL.

The composition may comprise 20 to 99.99% by weight; e.g. 30 to 99.99%by weight; e.g. 40 to 99.99% by weight; e.g. 50 to 99.99% by weight;e.g. 60 to 99.99% by weight; e.g. 70 to 99.99% by weight; e.g.75 to99.99% by weight; e.g. 20 to 60% by weight; e.g. 25 to 55% by weight 30to 50% by weight; e.g. about 20% by weight; e.g. 85 to 99.9%, e.g. 90 to99.5%, e.g. 92 to 97%, e.g. 93 to 96% by weight; of the sugar alcohol,e.g. of the mannitol, based on the total weight of the composition, e.g.of the final product suitable for oral administration or an intermediateform thereof. For example, it may comprise about e.g. about 25% byweight; e.g. about 30% by weight; e.g. about 35% by weight; e.g. about40% by weight; e.g. about 45% by weight; e.g. about 50% by weight; e.g.about 55% by weight; e.g. about 60% by weight, e.g. about 70% by weight,e.g. about 80% by weight e.g. about 90% by weight, e.g. about 92% byweight, e.g. about 94% by weight, e.g. about 95% by weight, e.g. about96% by weight, of the sugar alcohol, e.g. of the mannitol.

The composition preferably further comprises a lubricant. Suitablelubricants include stearic acid, magnesium stearate, calcium stearate,zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canolaoil, hydrogenated vegetable oil such as hydrogenated castor oil (e.g.Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulfate, magnesiumoxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol,polyvinyl alcohol, sodium benzoate, talc, poloxamer, or a mixture of anyof the above. For example the lubricant comprises magnesium stearate,hydrogenated castor oil, mineral oil, colloidal silicon dioxide,polyethylene glycol or a mixture thereof, e.g. magnesium stearate,hydrogenated castor oil, mineral oil or a mixture thereof. In a specificembodiment the lubricant consists of magnesium stearate, hydrogenatedcastor oil, mineral oil or a mixture thereof, e.g. consists of magnesiumstearate or a mixture of magnesium stearate with another lubricant.

The composition preferably comprises 0.01 to 5% by weight of thelubricant, e.g. of magnesium stearate, for example 0.5 to 3% by weight,1 to 2% by weight, e.g. about 3% by weight, e.g, about 2% by weight,about 1% by weight, about 0.5% by weight about 0.05% by weight, based onthe total weight of the composition.

The composition may comprise one or more further excipients such as abinder. The binder may be selected from polyvinyl pyrrolidone,methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,and mixture thereof. When used, the binder may be included in an amountof 1 to 8%, e.g. 3 to 6% by weight, based on the total weight of thecomposition.

The use of a binder increases the granule strength of the formulation,which is particularly important for fine granulations. Microcrystallinecellulose and methylcellulose are particularly preferred where a hightablet hardness and/or longer disintegration time is required.Hydroxypropyl cellulose may be preferred where faster distintegration isrequired. Where appropriate, xylitol may also be added as an additionalbinder, for example in addition to microcrystalline cellulose, e.g. inan amount up to 30% by weight , e.g. up to 20% by weight; e.g. up to 10%by weight of the sugar alcohol, e.g. mannitol or xylitol or mixturethereof.

The composition of the invention refers to a solid composition suitablefor oral administration, or to an intermediate form thereof, e.g. aformulation can be used to prepare a solid composition suitable for oraladministration The composition may be in the form of a soft gel, powder,granule or pellets or a unit dosage form, for example as a tablet orcapsule, e.g. a friezed dried tablet. The compositions of the presentinvention are well-adapted for encapsulation into an orallyadministrable capsule shell, particularly a hard gelatin shell or a HPMC(hypromellose) capsule. For example, it can be compositions that arefilled using the liquid dispensing technology for hard gelatin capsule.The solution containing the compound of the invention, may be dispensedin a capsule which is prefilled with the sugar alcohol as herein abovedefined, e.g. mannitol.

Alternatively the compositions may be compacted into tablets. Thetablets may optionally be coated, for instance with talc or apolysaccharide (e.g. cellulose) or hydroxypropylmethylcellulose coating.

The composition of the invention does not refer to an injection oranother parenteral composition.

Where the pharmaceutical composition is in unit dosage form, each unitdosage may contain 0.01 mg to 5 mg of the S1P receptor modulator, e.g.0.01 mg to 1 mg, e.g. 0.01 mg to 0.7 mg, e.g. 0.03 to 0.50 mg, e.g. 0.05mg to 0.50 mg, e.g. 0.06 mg to 0.50 mg, e.g. 0.10 mg to 0.50 mg, e.g.0.12 to 0.50 mg, e.g. 0.13 mg to 0.50 mg, e.g. 0.14 mg to 0.50 mg, e.g.0.15 mg to 0.50 mg, e.g. 0.16 mg to 0.50 mg, e.g. 0.17 mg to 0.50 mg,e.g. 0.18 mg to 0.50 mg, e.g. 0.19 mg to 0.50 mg, e.g. 0.20 mg to 0.50mg, e.g. 0.21 mg to 0.50 mg, e.g. to 0.22 mg to 0.50 mg, e.g. to 0.23 mgto 0.50 mg e.g. to 0.24 mg to 0.50 mg e.g. to 0.25 mg to 0.50 mg, e.g.to 0.26 mg to 0.50 mg, e.g. to 0.27 mg to 0.50 mg e.g. to 0.28 mg to0.50 mg, e.g. to 0.29 mg to 0.50 mg, e.g. to 0.30 mg to 0.50 mg, e.g. to0.32 mg to 0.50 mg, e.g. to 0.34 mg to 0.50 mg.

In another embodiment, each unit dosage may contain 0.01 mg to 0.40 mg,e.g. 0.02 mg to 0.40 mg, e.g. 0.03 mg to 0.40 mg, e.g. 0.06 mg to 0.40mg, e.g. 0.10 mg to 0.40 mg, e.g. 0.12 mg to 0.40 mg, e.g. 0.13 mg to0.40 mg, e.g. 0.14 mg to 0.40 mg, e.g. 0.15 mg to 0.40 mg, e.g. 0.16 mgto 0.40 mg, e.g. 0.17 mg to 0.40 mg, e.g. 0.18 mg to 0.40 mg, e.g. 0.20mg to 0.40 mg, e.g. 0.22 mg to 0.40 mg, e.g. 0.25 mg to 0.40 mg, e.g.0.30 mg to 0.40 mg, e.g. 0.35 mg to 0.40 mg.

In a further embodiment, each unit dosage may contain 0.050 mg to 0.350mg, e.g. 0.050 mg to 0.325 mg, e.g. 0.060 mg to 0.350 mg, e.g. 0.060 mgto 0.325 mg, e.g. 0.125 mg to 0.350 mg, e.g. 0.125 mg to 0.325 mg.

In a specific embodiment, each unit dosage contains about 0.125 mg,about 0.250 mg or about 0.500 mg.

In another specific embodiment, each unit dosage contains either about0.03 mg, about 0,06 mg, about 0.125 mg, about 0.250 mg, about 0.325 mgor about 0.500 mg.

For example, when is in unit dosage form, each unit dosage of thecomposition of the invention may contain about 0.50 mg, e.g. about 0.40mg, e.g. about 0.30 mg, e.g. about 0.25 mg, e.g. about 0.20 mg, e.g.about 0.15 mg, e.g. about 0.14 mg, e.g. about 0.13 mg, e.g. about 0.12mg, e.g. about 0.11 mg, e.g. about 0.10 mg, e.g. about 0.06 mg, e.g.about 0.05 mg, e.g. about 0.04 mg, e.g. about 0.03 mg, e.g. about 0.02mg, e.g. about 0.01 mg, e.g. about 0.375 mg, e.g. 0.325 mg, e.g. 0.175mg, e.g. about 0.135 mg, e.g. about 0.125 mg, e.g. about 0.115 mg, e.g.about 0.105 mg.

For example, the pharmaceutical composition of the invention is in unitdosage for, e.g. is a capsule or tablet, and comprises about 0.06 mg, orabout 0.125 mg, or about 0.250 mg, or about 0.325 mg or about 0.375 mgof the S1P receptor modulator of the invention, e.g.2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride.

The compositions of the invention may show good stabilitycharacteristics as indicated by standard stability trials, for examplehaving a shelf life stability of up to one, two or three years, and evenlonger. As herein defined, stable pharmaceutical compositions refer topharmaceutical compositions containing no impurities or impurities thatare present in an amount acceptable, e.g. on storage at roomtemperature, in particular in view of the Regulatory Health AuthoritiesRegulations and requirements. Stability characteristics may bedetermined, e.g. by measuring decomposition products by HPLC analysisafter storage for particular times, at particular temperatures, e.g.20°, 40° or 60° C., and/or under high humidity conditions.

The pharmaceutical compositions of the present invention may be producedby standard processes, for instance by conventional mixing, granulating,sugar-coating, dissolving or lyophilizing processes. Procedures whichmay be used are known in the art, e.g. those described in L. Lachman etal. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H.Sucker et al, Pharmazeutische Technologies, Thieme, 1991, HagersHandbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971)and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co.,1970) or later editions.

In one aspect, the present invention relates to a process for producinga pharmaceutical composition, comprising:

-   -   (a) mixing the stabilizer, e.g. a cyclodextrin, with S1P        receptor modulator; and optionally milling and/or granulating        the mixture obtained    -   (b) mixing the filler, e.g. the sugar alcohol, e.g. mannitol;        optionally milling and/or granulating the mixture obtained;    -   (c) optionally milling and/or granulating the mixture obtained        in (b); and    -   (d) mixing the milled and/or granulated mixture obtained in (b)        or (c) with a lubricant.

In step (b), the filler, e.g. the sugar alcohol, e.g. the mannitol, mayoptionally be milling and/or granulated before been mixed to the mixtureobtained in step (a).

In another embodiment of the invention, the composition of the inventionmay be produced by a process, comprising:

-   -   (a) mixing the stabilizer, e.g. a cyclodeytrin, with S1P        receptor modulator; and optionally milling and/or granulating        the mixture obtained    -   (a1) mixing the binder (e.g. hydroxypropyl cellulose) of the        invention with a sugar alcohol, e.g. mannitol; and optionally        milling and/or granulating the mixture obtained;    -   (b) mixing the mixtures obtained in step (a) and (a1);    -   (c) optionally milling and/or granulating the mixture obtained        in (b); and    -   (d) mixing the milled and/or granulated mixture obtained in (b)        or (c) with a lubricant.

By using this process, a preparation having a good level of content andblend uniformity (i.e. a substantially uniform distribution of the S1Preceptor modulator throughout the composition), dissolution time andstability is obtained.

The S1P receptor modulator, e.g.2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride, mayoptionally be micronized, and/or pre-screened, e.g. with a 400 to 500 μmmesh screen, before step (a) in order to remove lumps. The mixing step(a) may suitably comprise blending the S1P receptor modulator and thefiller, e.g. sugar alcohol, e.g. mannitol in any suitable blender ormixer for e.g. 100 to 400 revolutions.

The process may be carried out by dry mixing the components. In thisembodiment the milling step (a), (a1), or (c) may suitably comprisepassing the mixture obtained in (a) or (a1) through a screen, whichpreferably has a mesh size of 400 to 500 μm. Process step (a) maycomprise the step of mixing the total amount of S1P receptor modulatorat first with a cyclodextrin in order to form a pre-mix. Subsequentlythe required amount of sugar alcohol is added to the pre-mix.

Step (a), (a1) or (c) may also comprise the step of adding a bindersolution, e.g. methylcellulose and/or xylitol, e.g. an aqueous solution,to the mixture. Alternatively the binder is added to the mix dry andwater is added in the granulation step.

The milled mixture obtained in (a) or (a1) may optionally be blendedonce more before mixing with the lubricant. The lubricant, e.g.magnesium stearate, is preferably pre-screened, e.g. with a 800 to 900μm screen, before mixing.

Alternatively, a wet granulation process may be employed. In thisembodiment, the S1P receptor modulator is preferably solubilized in asolvent with the stabilizer, e.g. cyclodextrin and sprayed on thedry-mix of the desired filler, e.g. sugar alcohol, e.g. mannitol. Theobtained filler/S1P receptor modulator mixture, e.g. sugar alcohol/S1Preceptor modulator mixture, e.g. mannitol/S1P receptor modulatormixture, may then be dry-mixed with another binder such as e.g.hydroxypropyl cellulose or hydroxypropylmethyl cellulose. The solvent isthen added and the mixture granulated, e.g. using an automatedgranulator. The granulation is then dried and milled. The solvent may bewater.

Alternatively, a spray coating process may be employed. In thisembodiment the DS is solution (DS+CD) is sprayed on sugar beads ormannitol beads, the solvent is evaporate and the dried beads are thanencapsulated in hard gelatin or HPMC capsules. Solvents used to preparethe DS solution could be water (aqueous) or Ethanol (non-aqueous).

If desirable, an additional amount of binder may be added in step (d) tothe mixture obtained in (b).

The process may comprise a further step of tabletting or encapsulatingthe mixture obtained in (d), e.g. into a hard gelatin capsule using anautomated encapsulation device. The capsules may be coloured or markedso as to impart an individual appearance and to make them instantlyrecognizable. The use of dyes can serve to enhance the appearance aswell as to identify the capsules. Dyes suitable for use in pharmacytypically include carotinoids, iron oxides, and chlorophyll. Preferably,the capsules of the invention are marked using a code.

According to the invention, there is provided a process for producing asolid composition for oral administration of2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form, in apharmaceutically acceptable salt form or in a phosphate derivative form,comprising the steps of (i) mixing a compound selected from2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a pharmaceuticallyacceptable salt thereof, and a phosphate derivative thereof, with astabilizer, e.g. a cyclodextrin, in a solvent; (ii) mixing a filler,e.g. sugar alcohol, to the mixture obtained in step (i); (iii) addingthe solvent; (iv) granulating, (v) drying, milling, blending, and (vi)optionally tabletting or encapsulating.

Optionally a binder may be mixed, e.g. dry mixed, to the mixtureobtained in step (ii) and/or step (iii). In a specific embodiment, instep (ii) the used filler, e.g. the sugar alcohol, e.g. mannitol, isspray-dried.

By using this process, a preparation having a good level of content andblend uniformity (i.e. a substantially uniform distribution of the drugthroughout the composition), and stability is obtained.

The pharmaceutical compositions of the present invention are useful,either alone or in combination with other active agents, for thetreatment and prevention of conditions e.g. as disclosed in U.S. Pat.No. 5,604,229, WO 97/24112, WO 01/01978, U.S. Pat. No. 6,004,565, U.S.Pat. No. 6,274,629 and JP-14316985, the contents of which areincorporated herein by reference.

In particular, the pharmaceutical compositions are useful for:

a) treatment and prevention of organ or tissue transplant rejection, forexample for the treatment of the recipients of heart, lung, combinedheart-lung, liver, kidney, pancreatic, skin or corneal transplants, andthe prevention of graft-versus-host disease, such as sometimes occursfollowing bone marrow transplantation; particularly in the treatment ofacute or chronic allo- and xenograft rejection or in the transplantationof insulin producing cells, e.g. pancreatic islet cells;

b) treatment and prevention of autoimmune disease or of inflammatoryconditions, e.g. chronic long term diseases, e.g. multiple sclerosis,arthritis (for example rheumatoid arthritis), inflammatory boweldisease, hepatitis, etc.;

Multiple sclerosis takes several forms, with new symptoms occurringeither in discrete attacks (relapsing forms) or slowly accumulating overtime (progressive forms). As herein defined, multiple sclerosis refers,but is not limited to, relapsing remitting multiple sclerosis (RRMS) orprimary progressive multiple sclerosis (PPMS), e.g. RRMS.

According to the present invention the terms “treatment” or “treat”refer to both prophylactic or preventive treatment as well as curativeor disease-modifying treatment, including treatment of patients at riskof contracting the disease or disorder, or suspected to have contractedthe disease or disorder, as well as patients who are ill or have beendiagnosed as suffering from the disease or disorder.

As herein defined, treating multiple sclerosis refers to, but is notlimited to, reducing the frequency of clinical exacerbations, delayingthe progression of symptoms or disorders associated with multiplesclerosis or delaying the accumulation of physical disability induced bymultiple sclerosis.

Symptoms or disorders associated with multiple sclerosis encompassneurological symptoms, physical and cognitive disability andneuropsychiatric disorders.

Accordingly, in further aspects the present invention provides:

1. A composition as defined above, for use in treating or preventing adisease or condition as defined above.

2. A method of treating a subject in need of immunomodulation,comprising administering to the subject an effective amount of acomposition as defined above.

3. A method of treating or preventing a disease or condition as definedabove, comprising administering to the subject a composition as definedabove.

4. Use of a pharmaceutical composition as defined above for thepreparation of a medicament for the prevention or treatment of a diseaseor condition as defined above.

The invention will now be described with reference to the followingspecific embodiments.

EXAMPLE 1

FTY720 is dissolved in water to form approximately 20 percent (solutionA). HP-β CD is dissolved in water to form approximately 15 percent(solution B). Mannitol is added in a low shear granulator and sprayedsolutions A and B. The granulated material thus obtained is dried in atray dryer set at 60° C. The dried granules are then milled through aFrewitt mill attached with a 18 mesh screen. The milled granules areblended with magnesium stearate in a bin blender.

The lubricated granules are compressed to form tablets of the desireddose of 0.04 mg, and then encapsulated to achieve the desired dose of0.125 mg, containing:

TABLE 1 Quantity per Quantity per 0.040 mg mini- 0.125 mg Ingredientstablet (mg) capsule (mg) FTY720 HCl¹ 0.0448 0.140 Mannitol USP 3.75511.735 Hydroxy propyl beta cyclodextrin 0.120 0.375 (HP-β CD) MagnesiumStearate 0.040 0.125 ¹1.0 part of FTY720 is equivalent to 1.119 part ofFTY720 HCl salt

EXAMPLE 2

The composition with Hydroxy-beta-cyclodextrin in Example 1 is used toprocess the bulk powder for mini tablets and capsules.

TABLE 2 Blend uniformity assay results with total degradation products %FTY720 Mass Range/ Assay Total Degradation Balance Average 96.9 0.1 97.193.8- 95.7 0.1 95.9 99.2% 98.9 0.3 99.2 RSD: 2.3 93.6 0.2 93.8

Table 2 shows blend uniformity results for the final blend with an RSDof 2.3% indicating no segregation issues after final blending. The finalblend is then compressed in mini tablets and encapsulated.

The compressed tablets are of 4 mg in weight delivering a dose of 40micrograms of drug.

TABLE 3 stability under different conditions including stress conditionof 50° C./75% RH. % FTY720 Assay Total Deg Mass Balance StabilityCondition/ without with HP- with HP- Time Points with HP-β CD CD β CDwithout CD β CD without CD 0 week 100.19 95.02 0 0.0 100.2 95.050D-Dry/2 week 98.97 94.12 0.5 0.7 99.4 94.8 50D-75% RH/2 week 96.0490.88 1.5 1.2 97.6 92.1 50D-75% RH/12 wk 104.25 100.23 2.5 7.0 106.7107.2 25D/60% RH/4 week 100.20 93.86 1.2 0.5 101.4 94.3 50D-Dry/4 week99.04 93.99 0.6 1.4 99.6 95.4 50D-75% RH/4 week 95.94 87.23 1.4 2.4 97.489.6 CD = cyclodextrin

The data below shows a total degradation product of 1.4% at 50° C./75%RH for 4 weeks in the formulation with HP-β CD.

The capsules are encapsulated with a fill weight of 14 mg to deliver adose of 125 micrograms each. The table 4 summarizes the data forstability at different conditions including the stress conditions of 50°C./75% RH (Relative Humidity)

TABLE 4 Stability Condition/ % FTY720 Assay % Total Deg Mass BalanceTime Points Batch # with HP-β CD without CD with HP-β CD without CD withHP-β CD without CD 0 week 110.04 108.48 0 0 110.0 108.5 50D-Dry/2 week111.07 110.98 0.0 0.2 111.1 111.2 50D-75% RH/2 week 108.94 106.09 0.30.7 109.2 106.8 5D/12 wk 110.75 109.89 0.4 0.1 111.2 110.0 25D/60% RH/12wk 113.01 112.46 0.3 <LOQ 113.3 112.5 50D-Dry/12 wk 110.47 106.29 0.41.2 110.9 107.4 500-75% RH/12 wk 104.25 100.23 2.5 7.0 106.7 107.2

The data shows a total degradation product of 2.5% in the formulationwith HP-β CD.

Stability results in both tablets and capsules are indicative ofincreased stability of FTY720 in the drug product.

EXAMPLE 3

Hard gelatin capsules containing FTY720 are prepared as follow: HP-CDand FTY720 are dissolved in water to form approximately 20 percent(solution A). HPC is dissolved in water to form approximately 7 percent(solution B). Mannitol is added to a fluid bed drier and sprayed withsolutions A and B. The granulated material is than dried at a set inlettemperature of 65° C. in the fluid bed drier. The dried granules arethen milled through a Frewitt mill attached with a 18 mesh screen. Themilled granules are blended with magnesium stearate in a bin blender.The lubricated granules are encapsulated to obtain the desired dose of0.03 mg.

The same process is used to prepare the other capsules whose componentsare listed below:

TABLE 5 Composition of FTY720 0.03, 0.06 mg, 0.125 mg and 0.25 mgcapsules 0.03 mg 0.06 mg 0.125 mg 0.25 mg Ingredient capsule (mg)capsule (mg) capsule (mg) capsule (mg) FTY720 HCl ¹ 0.0336 0.0671 0.1400.280 Hydroxypropylcellulose 0.438 0.875 0.875 1.750 Hydroxypropyl-beta-0.145 0.289 0.301 0.603 cyclodextrin Mannitol 11.759 23.5189 23.43446.868 Magnesium Stearate ² 0.125 0.2500 0.250 0.500 Water, purified ³ —— — — Capsule fill weight 12.50 25.00 25.00 50.00 (theoretical weight)Empty capsule shell Weight of capsule shell 48.00 48.00 48.00 48.00Total weight 60.50 73.00 73.00 98.00 ¹ The molecular weight ratio ofFTY720 HCl to FTY720 base is approximately 1.12 to 1.0 ² Vegetableorigin ³ Used as a granulating aid and removed during processing.

1. A solid pharmaceutical composition suitable for oral administration,comprising a) a first compound selected from2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a pharmaceuticallyacceptable salt thereof, and a phosphate derivative thereof, b) afiller, and c) a stabilizer comprising a cyclodextrin or a derivativethereof.
 2. A composition according to claim 1, comprising less than1.5% or 1% by weight, e.g. 0.25% by weight or less, of the firstcompound, based on the total weight of the composition.
 3. A compositionaccording to claim 1, comprising 0.5 mg or less, of the first compound,4. A composition according to claim 1, wherein the filler comprises asugar alcohol, for example mannitol.
 5. A composition according to claim1, further comprising a binder, for example a binder comprisinghydroxypropyl cellulose.
 6. A composition according to claim 1, furthercomprising a lubricant, for example a lubricant comprising magnesiumstearate.
 7. A composition according to claim 1, wherein the stabilizercomprises hydroxypropyl-beta-cyclodextrin.
 8. A composition according toclaim 1, wherein the first compound is2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceuticallyacceptable salt thereof.
 9. A composition according to claim 1 fortreating an autoimmune disease.
 10. A method of treating an autoimmunedisease in a patient in need thereof, comprising administering atherapeutically effective amount of a compound selected from2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a pharmaceuticallyacceptable salt thereof, and a phosphate derivative thereof, with apharmaceutical composition as defined in claim 1.